Early brain injury linearly correlates with reduction in cerebral perfusion pressure during the hyperacute phase of subarachnoid hemorrhage

BACKGROUND It is unclear how complex pathophysiological mechanisms that result in early brain injury (EBI) after subarachnoid hemorrhage (SAH) are triggered. We investigate how peak intracranial pressure (ICP), amount of subarachnoid blood, and hyperacute depletion of cerebral perfusion pressure (CPP) correlate to the onset of EBI following experimental SAH. METHODS An entire spectrum of various degrees of SAH severities measured as peak ICP was generated and controlled using the blood shunt SAH model in rabbits. Standard cardiovascular monitoring, ICP, CPP, and bilateral regional cerebral blood flow (rCBF) were continuously measured. Cells with DNA damage and neurodegeneration were detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Fluoro-jade B (FJB). RESULTS rCBF was significantly correlated to reduction in CPP during the initial 15 min after SAH in a linear regression pattern (r (2) = 0.68, p < 0.001). FJB- and TUNEL-labeled cells were linearly correlated to reduction in CPP during the first 3 min of hemorrhage in the hippocampal regions (FJB: r (2) = 0.50, p < 0.01; TUNEL: r (2) = 0.35, p < 0.05), as well as in the basal cortex (TUNEL: r (2) = 0.58, p < 0.01). EBI occurred in animals with severe (relative CPP depletion >0.4) and moderate (relative CPP depletion >0.25 but <0.4) SAH. Neuronal cell death was equally detected in vulnerable and more resistant brain regions. CONCLUSIONS The degree of EBI in terms of neuronal cell degeneration in both the hippocampal regions and the basal cortex linearly correlates with reduced CPP during hyperacute SAH. Temporary CPP reduction, however, is not solely responsible for EBI but potentially triggers processes that eventually result in early brain damage.

Nitric oxide inhalation reduces brain damage, prevents mortality, and improves neurological outcome after subarachnoid hemorrhage by resolving early pial microvasospasms.

Subarachnoid hemorrhage is a stroke subtype with particularly bad outcome. Recent findings suggest that constrictions of pial arterioles occurring early after hemorrhage may be responsible for cerebral ischemia and - subsequently - unfavorable outcome after subarachnoid hemorrhage. Since we recently hypothesized that the lack of nitric oxide may cause post-hemorrhagic microvasospasms, our aim was to investigate whether inhaled nitric oxide, a treatment paradigm selectively delivering nitric oxide to ischemic microvessels, is able to dilate post-hemorrhagic microvasospasms; thereby improving outcome after experimental subarachnoid hemorrhage. C57BL/6 mice were subjected to experimental SAH. Three hours after subarachnoid hemorrhage pial artery spasms were quantified by intravital microscopy, then mice received inhaled nitric oxide or vehicle. For induction of large artery spasms mice received an intracisternal injection of autologous blood. Inhaled nitric oxide significantly reduced number and severity of subarachnoid hemorrhage-induced post-hemorrhage microvasospasms while only having limited effect on large artery spasms. This resulted in less brain-edema-formation, less hippocampal neuronal loss, lack of mortality, and significantly improved neurological outcome after subarachnoid hemorrhage. This suggests that spasms of pial arterioles play a major role for the outcome after subarachnoid hemorrhage and that lack of nitric oxide is an important mechanism of post-hemorrhagic microvascular dysfunction. Reversing microvascular dysfunction by inhaled nitric oxide might be a promising treatment strategy for subarachnoid hemorrhage.

Differences and similarities between spontaneous dissections of the internal carotid artery and the vertebral artery

Background and Purpose—To compare potential risk factors, clinical symptoms, diagnostic delay, and 3-month outcome between spontaneous internal carotid artery dissection (sICAD) and spontaneous vertebral artery dissection (sVAD). Methods—We compared patients with sICAD (n=668) and sVAD (n=302) treated in 3 university hospitals. Results—Patients with sICAD were older (46.3±9.6 versus 42.0±10.2 years; P<0.001), more often men (62.7% versus 53.0%; P=0.004), and presented more frequently with tinnitus (10.9% versus 3.4%; P<0.001) and more severe ischemic strokes (median National Institutes of Health Stroke Scale, 10±7.1 versus 5±5.9; P<0.001). Patients with sVAD had more often bilateral dissections (15.2% versus 7.6%; P<0.001) and were more often smokers (36.0% versus 28.7%; P=0.007). Thunderclap headache (9.2% versus 3.6%; P=0.001) and neck pain were more common (65.8% versus 33.5%; P<0.001) in sVAD. Subarachnoid hemorrhage (6.0% versus 0.6%; P<0.001) and ischemic stroke (69.5% versus 52.2%; P<0.001) were more frequent in sVAD. After multivariate analysis, sex difference lost its significance (P=0.21), and all other variables remained significant. Time to diagnosis was similar in sICAD and sVAD and improved between 2001 and 2012 compared with the previous 10-year period (8.0±10.5 days versus 10.7±13.2 days; P=0.004). In sVAD, favorable outcome 3 months after ischemic stroke (modified Rankin Scale, 0–2: 88.8% versus 58.4%; P<0.001), recurrent transient ischemic attack (4.8% versus 1.1%; P=0.001), and recurrent ischemic stroke (2.8% versus 0.7%; P=0.02) within 3 months were more frequent. Conclusions—sICAD and sVAD patients differ in many aspects. Future studies should perform separate analyses of these 2 entities.

Vertebral artery dissection: presenting findings and predictors of outcome

BACKGROUND AND PURPOSE: Few data exist about clinical, radiologic findings, clinical outcome, and its predictors in patients with spontaneous vertebral artery dissection (sVAD). METHODS: Clinical characteristics, imaging findings, 3-month outcomes, and its predictors were investigated in consecutive patients with sVAD. RESULTS: One hundred sixty-nine patients with 195 sVAD were identified. Brain ischemia occurred in 131 patients (77%; ischemic stroke, n=114, 67%; transient ischemic attack, n=17, 10%). Three patients with ischemic stroke showed also signs of subarachnoid hemorrhage (SAH); 3 (2%) had SAH without ischemia. The 134 patients with brain ischemia or SAH had head and/or neck pain in 118 (88%) and pulsatile tinnitus in seven (5%) patients. The remaining 35 patients (21%) had isolated head and/or neck pain in 21 (12%) cases, asymptomatic sVAD in 13 (8%), and cervical radiculopathy in one case (1%). Location of sVAD was more often in the pars transversaria (V2; 35%) or atlas loop (V3; 34%) than in the prevertebral (V1; 20%) or intracranial (V4; 11%) segment (P=0.0001). Outcome was favorable (modified Rankin scale score 0 or 1) in 88 (82%) of 107 ischemic stroke patients with follow up. Two (2%) patients died. Low baseline National Institutes of Health Stroke Scale score (P<0.0001) and younger age (P=0.007) were independent predictors of favorable outcome. CONCLUSIONS: sVAD is predominantly located in the pars transversaria (V2) or the atlas loop (V3). Most patients show posterior circulation ischemia. Favorable outcome is observed in most ischemic strokes and independently predicted by low National Institutes of Health Stroke Scale score and younger age.

Acute subdural hematoma from ruptured cerebral aneurysm

The combination of ruptured aneurysms with acute subdural hematomas (aSDHs) is a rare presentation. Patients with aSDH associated with aneurysmal bleeding represent a subgroup within the spectrum of aneurysmatic hemorrhage. We summarize the clinical characteristics, diagnostic evaluation, and management of a series of cases presenting with aSDH associated with aneurysmal subarachnoid hemorrhage (SAH).

Continuous intrathecal glyceryl trinitrate prevents delayed cerebral vasospasm in the single-SAH rabbit model in vivo

Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a major cause of high morbidity and mortality. The reduced availability of nitric oxide (NO) in blood and cerebrospinal fluid (CSF) is well established as a key mechanism of vasospasm. Systemic administration of glyceryl trinitrate (GTN), an NO donor also known as nitroglycerin, has failed to be established in clinical settings to prevent vasospasm because of its adverse effects, particularly hypotension. The purpose of this study was to analyze the effect of intrathecally administered GTN on vasospasm after experimental SAH in the rabbit basilar artery.

Outer skull landmark-based coordinates for measurement of cerebral blood flow and intracranial pressure in rabbits

Despite the increased use of intracranial neuromonitoring during experimental subarachnoid hemorrhage (SAH), coordinates for probe placement in rabbits are lacking. This study evaluates the safety and reliability of using outer skull landmarks to identify locations for placement of cerebral blood flow (CBF) and intraparenchymal intracranial pressure (ICP) probes. Experimental SAH was performed in 17 rabbits using an extracranial-intracranial shunt model. ICP probes were placed in the frontal lobe and compared to measurements recorded from the olfactory bulb. CBF probes were placed in various locations in the frontal cortex anterior to the coronary suture. Insertion depth, relation to the ventricular system, and ideal placement location were determined by post-mortem examination. ICP recordings at the time of SAH from the frontal lobe did not differ significantly from those obtained from the right olfactory bulb. Ideal coordinates for intraparenchymal CBF probes in the left and right frontal lobe were found to be located 4.6±0.9 and 4.5±1.2 anterior to the bregma, 4.7±0.7mm and 4.7±0.5mm parasagittal, and at depths of 4±0.5mm and 3.9±0.5mm, respectively. The results demonstrate that the presented coordinates based on skull landmarks allow reliable placement of intraparenchymal ICP and CBF probes in rabbit brains without the use of a stereotactic frame.

Unsecured intracranial aneurysms and induced hypertension in cerebral vasospasm: is induced hypertension safe?

Induced hypertension is an established therapy to treat cerebral vasospasm (CVS) following subarachnoid hemorrhage (SAH) to prevent delayed ischemic deficits. Currently, there is minimal evidence available assessing the risk of induced hypertension in the presence of unsecured aneurysms. The aim of this study was to investigate the impact of induced hypertension on the rupturing of unsecured aneurysms in treating CVS.

Clazosentan: prevention of cerebral vasospasm and the potential to overcome infarction

Cerebral vasospasm is a common complication occurring after aneurysmal subarachnoid hemorrhage (SAH). It is recognized as a leading preventable cause of morbidity and mortality in this patient group, but its management is challenging, and new treatments are needed. Clazosentan is an endothelin receptor antagonist designed to prevent endothelin-mediated cerebral vasospasm. Vajkoczy et al. (Neurosurg 103:9-17, 2005) initially demonstrated that clazosentan reduced moderate/severe angiographically proven vasospasm by 55% relative to placebo. These findings led to the initiation of the CONSCIOUS trial program to further examine the efficacy and safety of clazosentan in reducing angiographic vasospasm and improving clinical outcome after aneurysmal SAH. In the first of these studies, CONSCIOUS-1, 413 patients were randomized to placebo or clazosentan 1, 5 or 15 mg/h. Clazosentan reduced angiographic vasospasm dose-dependently relative to placebo with a maximum risk reduction of 65% with the highest dose. Despite this, there was no benefit of clazosentan on the secondary protocol-defined morbidity/mortality endpoint; however, additional post-hoc and modified endpoint analyses provided some evidence for a potential clinical benefit. Two additional large-scale studies (CONSCIOUS-2 and CONSCIOUS-3) are now underway to further investigate the potential of clazosentan to improve long-term clinical outcome.

Clinical assessment of deficits after SAH: hasty neurosurgeons and accurate neurologists

For survivors of aneurysmal subarachnoid hemorrhage (SAH), somatic and cognitive deficits can affect long-term outcomes. We were interested in comparing the deficits identified in SAH patients, including cognitive deficits, at discharge by neurosurgeons and deficits identified by neurologists upon admission to the rehabilitation unit on the same day. The assessment of deficits might have an impact on referring patients to rehabilitation. This retrospective study included 494 SAH patients treated between 2005 and 2010. Of these, 50 patients were discharged to an affiliated rehabilitation unit. Deficits were grouped into 18 categories and summarized into three groups: major somatic, minor somatic, and cognitive deficits. Major somatic deficits were identified in 16 and 20 patients (p = 0.53), minor somatic deficits in 16 and 44 (p < 0.0001) patients, and cognitive deficits in 36 and 45 (p < 0.04) patients by neurosurgeons and neurologists, respectively. The absolute number of deficits in daily activities identified by the neurosurgeon and neurologist were 21 and 31 major somatic deficits (p = 0.2), 18 and 97 minor somatic deficits (p < 0.0001), and 61 and 147 cognitive deficits (p < 0.0001), respectively. Significant differences in assessment of cognitive and minor somatic deficits between neurosurgeons and neurologists exist. Based on these findings, it is evident that for the neurosurgeon, there needs to be an increased awareness of the assessment of cognitive deficits and a more routine interdisciplinary approach, including the use of neuropsychological evaluations, to ensure a better triage of patients to rehabilitation or for discharge home.

Sequence variations in the von Hippel-Lindau tumor suppressor gene in patients with intracranial aneurysms

The rupture of intracranial aneurysms leads to subarachnoid hemorrhage, which is often associated with poor outcome. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the lack of candidate genes precludes identifying patients at risk by genetic analyses. We observed intracranial aneurysms in 2 patients with von Hippel-Lindau (VHL) disease and the known disease-causing mutation c.292T > C (p.Tyr98His) in the VHL tumor suppressor gene. This study investigates whether the VHL gene is a possible candidate gene for aneurysm formation.

Management of Patients Presenting with Acute Subdural Hematoma due to Ruptured Intracranial Aneurysm

Acute subdural hematoma is a rare presentation of ruptured aneurysms. The rarity of the disease makes it difficult to establish reliable clinical guidelines. Many patients present comatose and differential diagnosis is complicated due to aneurysm rupture results in or mimics traumatic brain injury. Fast decision-making is required to treat this life-threatening condition. Determining initial diagnostic studies, as well as making treatment decisions, can be complicated by rapid deterioration of the patient, and the mixture of symptoms due to the subarachnoid hemorrhage or mass effect of the hematoma. This paper reviews initial clinical and radiological findings, diagnostic approaches, treatment modalities, and outcome of patients presenting with aneurysmal subarachnoid hemorrhage complicated by acute subdural hematoma. Clinical strategies used by several authors over the past 20 years are discussed and summarized in a proposed treatment flowchart.

Automated, compliant, high-flow common carotid to middle cerebral artery bypass

The authors describe the use of the Cardica C-Port xA Distal Anastomosis System to perform an automated, high-flow extracranial-intracranial bypass. The C-Port system has been developed and tested in coronary artery bypass surgery for rapid distal coronary artery anastomoses. Air-powered, it performs an automated end-to-side anastomosis within seconds by nearly simultaneously making an arteriotomy and inserting 13 microclips into the graft and recipient vessel. Intracranial use of the device was first simulated in a cadaver prepared for microsurgical anatomical dissection. The authors used this system in a 43-year-old man who sustained a subarachnoid hemorrhage after being assaulted and was found to have a traumatic pseudoaneurysm of the proximal intracranial internal carotid artery. The aneurysm appeared to be enlarging on serial imaging studies and it was anticipated that a bypass would probably be needed to treat the lesion. An end-to-side bypass was performed with the C-Port system using a saphenous vein conduit extending from the common carotid artery to the middle cerebral artery. The bypass was demonstrated to be patent on intraoperative and postoperative arteriography. The patient had a temporary hyperperfusion syndrome and subsequently made a good neurological recovery. The C-Port system facilitates the performance of a high-flow extracranial-intracranial bypass with short periods of temporary arterial occlusion. Because of the size and configuration of the device, its use is not feasible in all anatomical situations that require a high-flow bypass; however it is a useful addition to the armamentarium of the neurovascular surgeon.

Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo

OBJECTIVE: Intrathecal bolus administration of nitric oxide donors and calcium channel antagonists has been proposed to reduce cerebral vasospasm (CVS) in animal subarachnoid hemorrhage (SAH) models. Intrathecal continuous administration of these substances for CVS prevention has not been extensively evaluated. This study compared the efficacy of continuous intrathecal infusions of the NO donor glyceroltrinitrate and nimodipine in preventing delayed CVS associated with SAH in an animal model in vivo. METHODS: New Zealand White rabbits were randomly assigned to six groups: no SAH/NaCl, no SAH/NO, no SAH/nimodipine, SAH/NaCl, SAH/NO, or SAH/nimodipine. Glyceroltrinitrate (GTN) at 0.5 microg/microl (0.5 microl/h) or nimodipine at 0.2 microg/microl (10 microl/h) or NaCl was continuously infused into the cisterna magna via an Alzet osmotic pump from day 0 to day 5 after injection of 1.0 ml autologous blood. The magnitude of spasm in the basilar artery was determined by comparison of pre- and posttreatment angiography and was calculated as proportional change in intraluminal diameter based on automatic measurements. RESULTS: A total of 55 experiments and 110 angiograms were performed. SAH was associated with vasoconstriction of the basilar artery (SAH/NaCl group 19.85+/-2.94%). Continuous intrathecal injection of GTN and nimodipine prevented SAH-induced CVS. There was significant prevention of CVS in animals treated with GTN (SAH/NO group 5.93+/-5.2%, n=11) and nimodipine (SAH/nimodipine group: 0.55+/-2.66%, n=9). There was no significant difference between the treatment groups and controls in prevention of CVS. CONCLUSIONS: This study demonstrates that prophylactic continuous intrathecal administration of either GTN or nimodipine equally prevents SAH-associated CVS in an animal model.

Postpartum cervicocephalic artery dissection

BACKGROUND AND PURPOSE: Cervicocephalic artery dissection (CAD) after childbirth is rare. The objective of this study was to determine differences between postpartum and nonpostpartum CAD. METHODS: We compared consecutive patients with postpartum CAD with a control group of women with nonpostpartum CAD. RESULTS: Of 245 patients with CAD, 102 women <50 years (6 with postpartum CAD and 96 with nonpostpartum CAD) were identified. Vascular risk factors and presenting characteristics did not differ significantly between postpartum CAD and nonpostpartum CAD women. By contrast, patients with postpartum CAD had more often coexisting conditions such as reversible cerebral vasoconstriction syndrome (2 of 6 versus 2 of 96; P=0.017), reversible posterior leukoencephalopathy syndrome (2 of 6 versus one of 96; P=0.009), and subarachnoid hemorrhage without signs of intracranial extension of CAD (2 of 6 versus zero of 96; P=0.003). CONCLUSIONS: CAD and associated conditions should be looked for in women with unusual headache after childbirth.